EA027493B1 - Intermediates for preparing an antiviral compound - Google Patents

Intermediates for preparing an antiviral compound Download PDF

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Publication number
EA027493B1
EA027493B1 EA201590073A EA201590073A EA027493B1 EA 027493 B1 EA027493 B1 EA 027493B1 EA 201590073 A EA201590073 A EA 201590073A EA 201590073 A EA201590073 A EA 201590073A EA 027493 B1 EA027493 B1 EA 027493B1
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EA
Eurasian Patent Office
Prior art keywords
aza
mmol
heptane
difluoro
spiro
Prior art date
Application number
EA201590073A
Other languages
Russian (ru)
Other versions
EA201590073A1 (en
Inventor
Хунянь Го
Дэррил Като
Торстен А. Киршберг
Хунтао Лю
Джон О. Линк
Майкл Л. Митчелл
Джей П. Перриш
Нил Сквайерс
Цзяньюй Сунь
Джеймс Тейлор
Элизабет М. Бейкон
Эда Каналес
Чон Ю. Ким
Эзоп Чо
Джероми Дж. Коттелл
Манодж С. Десай
Рэндалл Л. Хэлкомб
Эван С. Криговский
Скотт И. Лазервит
Ци Лю
Ричард Макман
Хьюн-Цзюн Пюнь
Джозеф Х. Сожье
Джеймс Д. Тренкл
Уинстон С. Це
Рэндалл В. Вивиан
Скотт Д. Шрёдер
Уильям Дж. Уоткинс
Ляньхун Сюй
Чжэн-Юй Ян
Терри Келлар
Сяонин Шэн
Майкл О'Нил Ханрахан Кларк
Чиэнь-хун Чоу
Майкл Грауп
Хаолунь Цзинь
Райан Макфадден
Майкл Р. Миш
Самуэль Е. Метобо
Бартон В. Филлипс
Чандрасекар Венкатарамани
Original Assignee
Джилид Фармассет Ллс
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Application filed by Джилид Фармассет Ллс filed Critical Джилид Фармассет Ллс
Publication of EA201590073A1 publication Critical patent/EA201590073A1/en
Publication of EA027493B1 publication Critical patent/EA027493B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

The invention is related to intermediates useful for preparing an anti-viral compound, such as (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluorene-2-yl)-1H-benzimidazole-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)carbamic acid methyl ester.

Description

Настоящее изобретение относится к промежуточным соединениям, предназначенным для получения противовирусного соединения, такого как (1-{3-[6-(9,9-дифтор-7-{2-[5-(2-метоксикарбониламино-3метил-бутирил)-5-аза-спиро[2.4]гепт-6-ил]-3Н-имидазол-4-ил}-9Н-флюорен-2-ил)-1Н-бензимидазол-2ил]-2-аза-бицикло[2.2.1]гептан-2-карбонил}-2-метил-пропил)-карбаминовой кислоты метиловый эфир.The present invention relates to intermediates for the preparation of an antiviral compound such as (1- {3- [6- (9,9-difluoro-7- {2- [5- (2-methoxycarbonylamino-3methyl-butyryl) -5 -az-spiro [2.4] hept-6-yl] -3H-imidazol-4-yl} -9H-fluoren-2-yl) -1H-benzimidazol-2yl] -2-aza-bicyclo [2.2.1] heptane -2-carbonyl} -2-methyl-propyl) -carbamic acid methyl ester.

Уровень техникиState of the art

Г епатит С известен как хроническое вирусное заболевание печени, характеризующееся заболеванием печени. Хотя лекарственные средства, действие которых направлено на печень, широко используются и продемонстрировали эффективность, их применение ограничено токсичностью и другими побочными 15 эффектами. Ингибиторы вируса гепатита С (ВГС) можно применять для контроля развития и прогрессирования инфекции, вызванной ВГС, а также в диагностических тестах на ВГС.Hepatitis C is known as a chronic viral liver disease characterized by liver disease. Although drugs that target the liver are widely used and have been shown to be effective, their use is limited by toxicity and other 15 side effects. Hepatitis C virus (HCV) inhibitors can be used to control the development and progression of HCV infection, as well as in diagnostic tests for HCV.

Существует потребность в новых терапевтических агентах против ВГС, методах их синтеза и новых промежуточных соединениях, предназначенных для их получения.There is a need for new anti-HCV therapeutic agents, methods for their synthesis, and new intermediates for their preparation.

Сущность изобретенияSUMMARY OF THE INVENTION

В одном варианте реализации настоящего изобретения предложено соединение, которое представляет собой 3-[6-(4,4,5,5-тетраметил-[1,3,2]диоксоборолан-2-ил)-1Н-бензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбоновой кислоты трет-бутиловый эфир формулыIn one embodiment, the invention provides a compound that is 3- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -1H-benzimidazol-2-yl] -2-aza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ether of the formula

В другом варианте реализации настоящего изобретения предложено соединение, которое представляет собой 6-[5-(7-бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-аза-спиро[2.4]гептан-5-карбоновой кислоты бензиловый эфир формулыIn another embodiment, the invention provides a compound that is 6- [5- (7-bromo-9,9-difluoro-9H-fluoren-2-yl) -1H-imidazol-2-yl] -5-aza spiro [2.4] heptane-5-carboxylic acid benzyl ester of the formula

В еще одном другом варианте реализации настоящего изобретения предложено соединение, которое представляет собой (1-{6-[5-(7-бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-азаспиро[2.4]гептан-5-карбонил}-2-метилпропил)карбаминовой кислоты метиловый эфир формулы:In yet another embodiment, the invention provides a compound that is (1- {6- [5- (7-bromo-9,9-difluoro-9H-fluoren-2-yl) -1H-imidazol-2-yl ] -5-azaspiro [2.4] heptane-5-carbonyl} -2-methylpropyl) carbamic acid methyl ester of the formula:

Все указанные выше соединения представляют собой промежуточные соединения, предназначенные для получения противовирусного соединения, такого как (1-{3-[6-(9,9-дифтор-7-{2-[5-(2-метоксикарбониламино-3-метил-бутирил)-5-аза-спиро[2.4]гепт-6-ил]-3Н-имидазол-4-ил}-9Н-флюорен-2-ил)-1Нбензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбонил}-2-метилпропил)карбаминовой кислоты метиловый эфир, синтез которого осуществляют по схеме, представленной в примере ΕΌ'.All of the above compounds are intermediates for the preparation of an antiviral compound such as (1- {3- [6- (9,9-difluoro-7- {2- [5- (2-methoxycarbonylamino-3-methyl- butyryl) -5-aza-spiro [2.4] hept-6-yl] -3H-imidazol-4-yl} -9H-fluoren-2-yl) -1Nbenzimidazol-2-yl] -2-aza-bicyclo [2.2 .1] heptane-2-carbonyl} -2-methylpropyl) carbamic acid methyl ester, the synthesis of which is carried out according to the scheme presented in example ΕΌ '.

- 1 027493- 1 027493

Пример ΕΌ'Example ΕΌ '

2,7-Дибром-9,9-дифтор-9Н-флюорен2,7-Dibromo-9,9-difluoro-9H-fluorene

2.7- дибром-флюорен-9-он (4.0 г, 11.8 ммоль) суспендировали в деоксофторе (12 мл) при комнатной температуре и добавляли ΕΐΟΗ (4 капли). Перемешиваемую суспензию нагревали при Т=90°С в течение 24 ч (Предупреждение: Использование деоксофтора при повышенных температурах, как описано выше, настоятельно не рекомендуется, поскольку может возникнуть бурный экзотермический процесс).2.7-dibromo-fluoren-9-one (4.0 g, 11.8 mmol) was suspended in deoxofluor (12 ml) at room temperature and ΕΐΟΗ (4 drops) was added. The stirred suspension was heated at T = 90 ° C for 24 hours (Warning: Using deoxofluoride at elevated temperatures, as described above, is strongly discouraged, as a violent exothermic process may occur).

Реакционную смесь охлаждали до комнатной температуры и выливали на лёд содержащий бикарбонат натрия. Полученное твёрдое вещество собирали фильтрацией. Сырой материал разбавляли в ЕЮАс и промывали водным раствором НС1 (1М) и раствором хлорида натрия. Раствор сушили на сульфате натрия. Фильтрация и выпаривание растворителей давали сырой продукт, который очищали путем хроматографии на силикагеле (элюент: ЕЮАс/гексаны) с получением продукта 2,7-дибром-9,9-дифтор9Н-флюорен (3.2 г). 19Ρ-ΝΜΚ: 282 МГц, (ДМСО-б6) δ: -111.6 ррт. Полученный материал использовали на следующем этапе, где его в виде раствора в ЕЮАс обрабатывали углём.The reaction mixture was cooled to room temperature and poured onto ice containing sodium bicarbonate. The resulting solid was collected by filtration. The crude material was diluted in EJAc and washed with aqueous HC1 (1M) and sodium chloride solution. The solution was dried on sodium sulfate. Filtration and evaporation of the solvents gave a crude product, which was purified by silica gel chromatography (eluent: EluAc / Hexanes) to give 2,7-dibromo-9,9-difluoro9H-fluorene (3.2 g). 19 Ρ-ΝΜΚ: 282 MHz, (DMSO-b 6 ) δ: -111.6 ppm. The resulting material was used in the next step, where it was treated with coal in the form of a solution in EJAc.

5-Аза-спиро[2.4]гептан-5,6-дикарбоксильная кислота 5-бензилового эфира 6-[2-(7-бром-9,9-дифтор-9Н-флюорен-2-ил)-2-оксо-этил] эфир5-Aza-spiro [2.4] heptane-5,6-dicarboxylic acid 5-benzyl ester 6- [2- (7-bromo-9,9-difluoro-9H-fluoren-2-yl) -2-oxo-ethyl ] ether

2.7- Дибром-9,9-дифтор-9Н-флюорен (372 мг, 1.04 ммоль), Рб(РРй3)4 (30.0 мг, 0.026 ммоль), РбС12(РРй3)2 (18.2 мг, 0.026 ммоль), Ак(РРй3)3 (5.0 мг) растворяли в диоксане (10 мл) в атмосфере аргона. Добавляли этоксивинил-трибутил олово (376.4 мг, 1.04 ммоль). Смесь нагревали в течение 140 мин при 85°С (масляная баня). Реакционную смесь охлаждали до комнатной температуры. Добавляли Ν-бром сукцинимид (177 мг, 1.0 ммоль), а затем воду (2 мл). Реакционную смесь перемешивали при комнатной температуре в течение 3 ч, после чего большую часть диоксана удаляли в вакууме. Сырую реакционную смесь разбавляли ЕЮАс и промывали водой. Все летучие вещества удаляли в вакууме. Добавляли толуол и повторно удаляли все летучие вещества в вакууме. Сырой материал растворяли в ДМФ/ ΜеСN (2 мл, 1:1) при комнатной температуре, раствор ЖСЬ/-4-циклопропил (Ь) пролина (0.84 ммоль) и ДИЭФ (2682.7- Dibromo-9.9-difluoro-9H-fluorene (372 mg, 1.04 mmol), Rb (PPy 3 ) 4 (30.0 mg, 0.026 mmol), PbCl 2 (PPy 3 ) 2 (18.2 mg, 0.026 mmol), Ak (PPy 3 ) 3 (5.0 mg) was dissolved in dioxane (10 ml) in an argon atmosphere. Ethoxyvinyl tributyl tin (376.4 mg, 1.04 mmol) was added. The mixture was heated for 140 min at 85 ° C (oil bath). The reaction mixture was cooled to room temperature. S-bromine succinimide (177 mg, 1.0 mmol) was added, followed by water (2 ml). The reaction mixture was stirred at room temperature for 3 hours, after which most of the dioxane was removed in vacuo. The crude reaction mixture was diluted with EAAc and washed with water. All volatiles were removed in vacuo. Toluene was added and all volatiles were removed again in vacuo. The crude material was dissolved in DMF / FeCN (2 ml, 1: 1) at room temperature, a solution of LCI / -4-cyclopropyl (L) proline (0.84 mmol) and DIEF (268

- 2 027493 мг, 2.08 ммоль) в МеСЫ (2 мл) добавляли и продолжали перемешивать при комнатной температуре. Через 14 ч большую часть МеСЫ удаляли в вакууме и сырую реакционную смесь разбавляли ЕЮАс. Смесь промывали водным раствором НС1 (1М), водным раствором ЫС1 (5%), раствором хлорида натрия и сушили на сульфате натрия. Фильтрация и выпаривание растворителей давали сырой продукт реакции, который очищали путем хроматрографии на силикагеле (элюент: ЕЮАс/гексаны) с получением продукта 5-аза-спиро[2.4]гептан-5,6-дикарбоксильная кислота 5-бензилового эфира 6-[2-(7-бром-9,9-дифтор-9Нфлюорен-2-ил)-2-оксо-этил]эфира (176 мг). ЖХ-МС-Е8Е: расч. для С30Н24ВгР2ХО5: 596.4 (М+); Эксп.: 595.2 / 597.2 (М+Н+).- 2 027493 mg, 2.08 mmol) in MESA (2 ml) was added and stirring was continued at room temperature. After 14 hours, most of the MeCA was removed in vacuo and the crude reaction mixture was diluted with EuAc. The mixture was washed with an aqueous solution of HC1 (1M), an aqueous solution of HC1 (5%), a solution of sodium chloride and dried on sodium sulfate. Filtration and evaporation of the solvents gave a crude reaction product, which was purified by chromatography on silica gel (eluent: ЕУАс / hexanes) to obtain the product 5-aza-spiro [2.4] heptane-5,6-dicarboxylic acid 5-benzyl ether 6- [2- (7-bromo-9,9-difluoro-9N-fluoren-2-yl) -2-oxo-ethyl] ether (176 mg). LC-MS-E8E: calc. for C 30 H 24 VgR 2 XO 5 : 596.4 (M +); Exp .: 595.2 / 597.2 (M + H +).

6-[5-(7-Бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-аза-спиро[2.4]гептан-5-карбоновой кислоты бензиловый эфир6- [5- (7-Bromo-9,9-difluoro-9H-fluoren-2-yl) -1H-imidazol-2-yl] -5-aza-spiro [2.4] heptane-5-carboxylic acid benzyl ester

5- Аза-спиро[2.4]гептан-5,6-дикарбоксильная кислота 5-бензилового эфира 6-[2-(7-бром-9,9-дифтор9Н-флюорен-2-ил)-2-оксо-этил] эфир (172 мг, 0.293 ммоль) растворяли в т-ксиленах (6.0 мл). Добавляли ацетат аммония (226 мг, 2.93 ммоль) и перемешивали реакционную смесь при 140°С в течение 60 мин под действием микроволнового излучения. Реакционную смесь охлаждали до комнатной температуры и все летучие вещества удаляли в вакууме. Сырой материал очищали путем хроматрографии на силикагеле (элюент: ЕЮАс/гексаны) с получением продукта 6-[5-(7-бром-9,9-дифтор-9Н-флюорен-2-ил)-1Нимидазол-2-ил]-5-аза-спиро[2.4]гептан-5-карбоновой кислоты бензилового эфира (80.3 мг). ЖХ-МСЕ81+: расч. для С30Н24ВгР2И3О2: 576.4 (М+); Эксп.: 575.2/577.2 (М+Н+).5- Aza-spiro [2.4] heptane-5,6-dicarboxylic acid 5-benzyl ester 6- [2- (7-bromo-9,9-difluoro9H-fluoren-2-yl) -2-oxoethyl] ether (172 mg, 0.293 mmol) was dissolved in t-xylenes (6.0 ml). Ammonium acetate (226 mg, 2.93 mmol) was added and the reaction mixture was stirred at 140 ° C for 60 minutes under the influence of microwave radiation. The reaction mixture was cooled to room temperature and all volatiles were removed in vacuo. The crude material was purified by chromatography on silica gel (eluent: EJAc / hexanes) to give the product 6- [5- (7-bromo-9,9-difluoro-9H-fluoren-2-yl) -1Nimidazol-2-yl] -5 -az-spiro [2.4] heptane-5-carboxylic acid benzyl ether (80.3 mg). LC-MCE81 +: calc. for C 30 H 24 VgR 2 And 3 O 2 : 576.4 (M +); Exp .: 575.2 / 577.2 (M + H +).

(1-{6-[5-(7-Бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-аза-спиро[2.4]гептан-5-карбонил}2-метилпропил)карбаминовой кислоты метиловый эфир(1- {6- [5- (7-Bromo-9,9-difluoro-9H-fluoren-2-yl) -1H-imidazol-2-yl] -5-aza-spiro [2.4] heptane-5- carbonyl} 2-methylpropyl) carbamic acid methyl ester

6- [5-(7-Бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-аза-спиро[2.4]гептан-5карбоновой кислоты бензиловый эфир (800 мг, 1.38 ммоль) растворяли в ДХМ (15 мл), добавляли НВг в АсОН (37%, 2 мл) и продолжали перемешивать при комнатной температуре. Через 180 мин суспензию разбавляли гексанами, собирали твердое вещество фильтрацией и промывали гексанами в вакууме. Сырой материал использовали на следующем этапе без дополнительной очистки. Сырой материал растворяли в ДМФ(4.0 мл) и ДИЭА (356 мг, 2.76 ммоль), добавляли раствор 2-(Ь)-метоксикарбониламино-3метил-масляной кислоты (242 мг, 1.38 ммоль), НАТИ (524 мг, 1.38 ммоль) и добавляли ДИЭА (178 мг, 1.38 ммоль) в ДМФ(1 мл). Реакционную смесь перемешивали при комнатной температуре. Через 50 мин реакционную смесь разбавляли ЕЮАс и промывали водным раствором бикарбоната, водным раствором ЫС1 (5%), раствором хлорида натрия и сушили на сульфате натрия. Фильтрация и удаление растворителей в вакууме давали неочищенный материал, который очищали путем хроматографии на силикагеле (элюент: ЕЮАс/гексаны) с получением содержащего небольшое количество примесей продукта (1-{6-[5(7-бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-аза-спиро[2,4]гептан-5-карбонил}-2-метилпропил)карбаминовой кислоты метилового эфира (878 мг). ЖХ-МС-Е81+: расч. для С29Н29ВгР2Х.Ю3: 599.5 (М+); Эксп.: 598.5/600.5 (М+Н+).6- [5- (7-Bromo-9,9-difluoro-9H-fluoren-2-yl) -1H-imidazol-2-yl] -5-aza-spiro [2.4] heptane-5carboxylic acid benzyl ester (800 mg, 1.38 mmol) was dissolved in DCM (15 ml), HBg in AcOH (37%, 2 ml) was added and stirring was continued at room temperature. After 180 minutes, the suspension was diluted with hexanes, the solid was collected by filtration and washed with hexanes in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 ml) and DIEA (356 mg, 2.76 mmol), a solution of 2- (b) -methoxycarbonylamino-3-methyl-butyric acid (242 mg, 1.38 mmol), NATI (524 mg, 1.38 mmol) was added and DIEA (178 mg, 1.38 mmol) in DMF (1 ml) was added. The reaction mixture was stirred at room temperature. After 50 min, the reaction mixture was diluted with EuAc and washed with an aqueous solution of bicarbonate, an aqueous solution of LiCl (5%), a solution of sodium chloride and dried on sodium sulfate. Filtration and removal of solvents in vacuo afforded the crude material, which was purified by silica gel chromatography (eluent: EuAc / Hexanes) to give a small amount of impurities product (1- {6- [5 (7-bromo-9.9-difluoro-9H) -fluoren-2-yl) -1H-imidazol-2-yl] -5-aza-spiro [2,4] heptane-5-carbonyl} -2-methylpropyl) carbamic acid methyl ester (878 mg). LC-MS-E81 +: calc. for С 29 Н 29 ВрР 2 Х.Ю 3 : 599.5 (M + ); Exp .: 598.5 / 600.5 (M + H + ).

3-[6-(9,9-Дифтор-7-{2-[5-(2-метоксикарбониламино-3-метил-бутирил)-5-аза-спиро[2.4]гепт-6-ил]-3Нимидазол-4-ил}-9Н-флюорен-2-ил)-1Н-бензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбоновой кислоты трет-бутиловый эфир:3- [6- (9,9-Difluoro-7- {2- [5- (2-methoxycarbonylamino-3-methyl-butyryl) -5-aza-spiro [2.4] hept-6-yl] -3Nimidazole-4 -yl} -9H-fluoren-2-yl) -1H-benzimidazol-2-yl] -2-aza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ether:

(1-{6-[5-(7-Бром-9,9-дифтор-9Н-флюорен-2-ил)-1Н-имидазол-2-ил]-5-аза-спиро[2.4]гептан-5карбонил}-2-метилпропил)карбаминовой кислоты метиловый эфир (840 мг, 1.4 ммоль), 3-[6-(4,4,5,5тетраметил-[1,3,2]диоксоборолан-2-ил)-1Н-бензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбоновой кислоты трет-бутиловый эфир (615 мг, 1.4 ммоль), РД(РРй3)4 (161 мг, 0.14 ммоль), К2СО3 (579 мг, 4.2 ммоль), растворяли в смеси ИМЕ (15 мл) / вода (3 мл) в атмосфере аргона. Смесь нагревали в течение 120 мин при 85-90°С (масляная баня). Через 120 мин добавляли дополнительный боронат эфир (61 мг, 0.14 ммоль) и продолжали нагревать. Через 3 ч реакционную смесь охлаждали до комнатной температуры. Большую часть ИМЕ удаляли в вакууме и сырую реакционную смесь разбавляли ЕЮАс. Смесь промывали раствором хлорида натрия и сушили на сульфате натрия. Фильтрация и выпаривание растворителей давали сырой продукт реакции, который очищали путем хроматрографии на силикагеле (элюент: ЕЮАс/гексаны) с получением продукта 3-[6-(9,9-дифтор-7-{2-[5-(2-метоксикарбониламино-3-метилбутирил)-5-аза-спиро[2.4]гепт-6-ил]-3Н-имидазол-4-ил}-9Н-флюорен-2-ил)-1Н-бензимидазол-2-ил]-2аза-бицикло[2.2.1]гептан-2-карбоновой кислоты трет-бутилового эфира (878 мг). ЖХ-МС-Е8Е: расч. для С47Н51Р2Н7О5: 831.9 (М +); Эксп.: 832.7 (М+Н+).(1- {6- [5- (7-Bromo-9,9-difluoro-9H-fluoren-2-yl) -1H-imidazol-2-yl] -5-aza-spiro [2.4] heptane-5carbonyl} -2-methylpropyl) carbamic acid methyl ester (840 mg, 1.4 mmol), 3- [6- (4,4,5,5tetramethyl- [1,3,2] dioxoborolan-2-yl) -1H-benzimidazol-2 -yl] -2-aza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ether (615 mg, 1.4 mmol), RD (PPY 3 ) 4 (161 mg, 0.14 mmol), K 2 CO 3 (579 mg, 4.2 mmol) was dissolved in a mixture of IME (15 ml) / water (3 ml) in an argon atmosphere. The mixture was heated for 120 min at 85-90 ° C (oil bath). After 120 minutes, additional boronate ether (61 mg, 0.14 mmol) was added and continued heating. After 3 hours, the reaction mixture was cooled to room temperature. Most IMEs were removed in vacuo and the crude reaction mixture was diluted with EAAc. The mixture was washed with sodium chloride solution and dried on sodium sulfate. Filtration and evaporation of the solvents gave a crude reaction product, which was purified by chromatography on silica gel (eluent: EuAc / Hexanes) to give the product 3- [6- (9,9-difluoro-7- {2- [5- (2-methoxycarbonylamino 3-methylbutyryl) -5-aza-spiro [2.4] hept-6-yl] -3H-imidazol-4-yl} -9H-fluoren-2-yl) -1H-benzimidazol-2-yl] -2aza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ether (878 mg). LC-MS-E8E: calc. for C 47 H5 1 P 2 H 7 O 5 : 831.9 (M +); Exp .: 832.7 (M + H +).

(1-{3-[6-(9,9-Дифтор-7-{2-[5-(2-метоксикарбониламино-3-метил-бутирил)-5-аза-спиро[2.4]гепт-6-ил]-3Нимидазол-4-ил}-9Н-флюорен-2-ил)-1Н-бензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбонил}-2метилпропил)карбаминовой кислоты метиловый эфир(1- {3- [6- (9,9-Difluoro-7- {2- [5- (2-methoxycarbonylamino-3-methyl-butyryl) -5-aza-spiro [2.4] hept-6-yl] -3Nimidazol-4-yl} -9H-fluoren-2-yl) -1H-benzimidazol-2-yl] -2-aza-bicyclo [2.2.1] heptane-2-carbonyl} -2methylpropyl) carbamic acid methyl ester

3-[6-(9,9-Дифтор-7-{2-[5-(2-метоксикарбониламино-3-метил-бутирил)-5-аза-спиро[2.4]гепт-6-ил]3Н-имидазол-4-ил}-9Н-флюорен-2-ил)-1Н-бензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбоновой кислоты трет-бутиловый эфир (115 мг, 0.138 ммоль) растворяли в ДХМ (2 мл), добавляли НС1 в диоксане (4М, 2 мл) и продолжали перемешивать при комнатной температуре. Через 20 мин все летучие вещества удаляли в вакууме. Сырой материал использовали на следующем этапе без дополнительной очистки. Сырой материал растворяли в ДМФ (1.5 мл) и ДИЭА (53.4 мг, 0.414 ммоль) добавляли раствор 2-(Ь) ме- 3 027493 токсикарбониламино-3-метил-масляной кислоты (24.2 мг, 0.138 ммоль), НАТИ (52.4 мг, 0.138 ммоль) и добавляли ДИЭА (17.8 мг, 0.138 ммоль) в ДМФ(1 мл). Реакционную смесь перемешивали при комнатной температуре. Через 20 мин реакционную смесь разбавляли ЕЮАс и промывали водным раствором бикарбоната, водным раствором ЫС1 (5%), раствором хлорида натрия и сушили на сульфате натрия. Фильтрация и удаление растворителей в вакууме давали неочищенный материал, который очищали путём ОФ-ВЭЖХ (элюент: вода/МеСЫ№/0.1% ТФА) с получением продукта (1-{3-[6-(9,9-дифтор-7-{2-[5(2-метоксикарбониламино-3-метил-бутирил)-5-аза-спиро[2.4]гепт-6-ил]-3Н-имидазол-4-ил}-9Н-флюорен-2-ил)-1Н-бензимидазол-2-ил]-2-аза-бицикло[2.2.1]гептан-2-карбонил}-2-метилпропил)карбаминовой кислоты метилового эфира (76 мг). ЖХ-МС-Е31+: расч. для С49Н54Р2Н8О6: 888.9 (М+); Эксп.: 890.0 (М+Н+).3- [6- (9,9-Difluoro-7- {2- [5- (2-methoxycarbonylamino-3-methyl-butyryl) -5-aza-spiro [2.4] hept-6-yl] 3H-imidazole- 4-yl} -9H-fluoren-2-yl) -1H-benzimidazol-2-yl] -2-aza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ether (115 mg, 0.138 mmol) dissolved in DCM (2 ml), HC1 in dioxane (4M, 2 ml) was added and stirring was continued at room temperature. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 ml) and DIEA (53.4 mg, 0.414 mmol) was added a solution of 2- (b) methoxycarbonylamino-3-methylbutyric acid (24.2 mg, 0.138 mmol), NATI (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 ml) was added. The reaction mixture was stirred at room temperature. After 20 minutes, the reaction mixture was diluted with EuAc and washed with an aqueous bicarbonate solution, an aqueous solution of LiCl (5%), a solution of sodium chloride and dried on sodium sulfate. Filtration and removal of solvents in vacuo afforded the crude material, which was purified by RP-HPLC (eluent: water / MeCl # / 0.1% TFA) to give the product (1- {3- [6- (9.9-difluoro-7- { 2- [5 (2-methoxycarbonylamino-3-methyl-butyryl) -5-aza-spiro [2.4] hept-6-yl] -3H-imidazol-4-yl} -9H-fluoren-2-yl) -1H -benzimidazol-2-yl] -2-aza-bicyclo [2.2.1] heptane-2-carbonyl} -2-methylpropyl) carbamic acid methyl ester (76 mg). LC-MS-E31 +: calc. for C 49 H 54 P 2 H 8 O 6 : 888.9 (M +); Exp .: 890.0 (M + H +).

' 11-ЯМР: 300 МГц, (ДМСО-й6) δ: 8.20-7.99 (т, 8Н), 7.73 (к, 2Н), 7.37-7.27 (т, 2Н), 5.25 (άά, 1-7.2 Гц, 1Н), 4.78 (к, 1Н) 4.54 (к, 1Н), 4.16 (т, 1Н), 4.02 (т, 1Н), 3.87 (т, 1Н), 3.74 (т, 1Н), 3.55 (к, 3Н), 3.53 (к, 3Н), 2.75 (т, 1Н), 2.25 (т, 2Н), 2.09-2.04 (т, 2Н), 1.88-1.79 (т, 2Н), 1.54 (т, 1Н), 0.94-0.77 (т, 15Н) 0.63 (т, 4ч) ррт. Р-ХМН: 282 МГц, (ДМСО^6) δ: -109.1 ррт [-74.8 ррт ТФА].'11-NMR: 300 MHz, (DMSO 6th ) δ: 8.20-7.99 (t, 8H), 7.73 (q, 2H), 7.37-7.27 (t, 2H), 5.25 (άά, 1-7.2 Hz, 1H), 4.78 (q, 1H) 4.54 (q, 1H), 4.16 (t, 1H), 4.02 (t, 1H), 3.87 (t, 1H), 3.74 (t, 1H), 3.55 (q, 3H) , 3.53 (q, 3H), 2.75 (t, 1H), 2.25 (t, 2H), 2.09-2.04 (t, 2H), 1.88-1.79 (t, 2H), 1.54 (t, 1H), 0.94-0.77 (t, 15H) 0.63 (t, 4h) ppm. R-CMS: 282 MHz, (DMSO ^ 6 ) δ: -109.1 ppm [-74.8 ppm TFA].

Claims (1)

Соединение формулыCompound of the formula Соединение формулыCompound of the formula ВгVg Соединение формулыCompound of the formula ВгVg
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Families Citing this family (202)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100503628C (en) 2003-05-30 2009-06-24 法莫赛特股份有限公司 Modified fluorinated nucleoside analogues
CN103396409B (en) * 2007-07-05 2015-03-11 阵列生物制药公司 Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
CA2745119A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
CN104163816A (en) * 2008-12-03 2014-11-26 普雷西迪奥制药公司 Inhibitors of HCV NS5A
EP2367824B1 (en) 2008-12-23 2016-03-23 AbbVie Inc. Anti-viral derivatives of pyrimidine
CN102245604A (en) 2008-12-23 2011-11-16 雅培制药有限公司 Anti-viral compounds
US8314135B2 (en) 2009-02-09 2012-11-20 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole antivirals
TWI438200B (en) * 2009-02-17 2014-05-21 必治妥美雅史谷比公司 Hepatitis c virus inhibitors
US8242156B2 (en) 2009-02-17 2012-08-14 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole derivatives
US8637561B2 (en) * 2009-02-17 2014-01-28 Enanta Pharmaceuticals, Inc. Linked diimidazole derivatives
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8188132B2 (en) 2009-02-17 2012-05-29 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole derivatives
US20120040977A1 (en) * 2009-02-23 2012-02-16 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
US8101643B2 (en) * 2009-02-27 2012-01-24 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US8673954B2 (en) 2009-02-27 2014-03-18 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US9765087B2 (en) 2009-02-27 2017-09-19 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
EP2410841A4 (en) 2009-03-27 2012-10-24 Presidio Pharmaceuticals Inc Substituted bicyclic hcv inhibitors
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
TW201038559A (en) * 2009-04-09 2010-11-01 Bristol Myers Squibb Co Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
MX2011010905A (en) 2009-04-15 2011-11-01 Abbott Lab Anti-viral compounds.
CN102414199B (en) * 2009-04-24 2014-03-05 泰博特克药品公司 Diaryl ethers
US9139569B2 (en) * 2009-05-12 2015-09-22 Merck Sharp & Dohme Corp. Fused tricyclic aryl compounds useful for the treatment of viral diseases
EP2857394A1 (en) 2009-05-13 2015-04-08 Gilead Pharmasset LLC Antiviral compounds
US8138215B2 (en) * 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010138791A1 (en) * 2009-05-29 2010-12-02 Schering Corporation Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
AU2010253790A1 (en) * 2009-05-29 2011-12-15 Merck Sharp & Dohme Corp. Antiviral compounds composed of three aligned aryl moieties to treat diseases such as Hepatitis C
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
US9394279B2 (en) 2009-06-11 2016-07-19 Abbvie Inc. Anti-viral compounds
EP2337781B1 (en) * 2009-06-11 2014-07-23 AbbVie Bahamas Ltd. Anti-viral compounds to treat hcv infection
US8716454B2 (en) 2009-06-11 2014-05-06 Abbvie Inc. Solid compositions
US8609648B2 (en) 2009-07-02 2013-12-17 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
AU2010274001A1 (en) 2009-07-16 2012-02-23 Vertex Pharmaceuticals Incorporated Benzimidazole analogues for the treatment or prevention of Flavivirus infections
AU2010280711A1 (en) * 2009-08-07 2012-02-09 Janssen Sciences Ireland Uc Phenyl ethynyl derivatives as hepatitis C virus inhibitors
CA2768638A1 (en) * 2009-08-07 2011-02-10 Tibotec Pharmaceuticals Bis-benzimidazole derivatives as hepatitis c virus inhibitors
SG178952A1 (en) 2009-09-04 2012-04-27 Glaxosmithkline Llc Chemical compounds
US8927709B2 (en) * 2009-09-11 2015-01-06 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011031934A1 (en) * 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US8815928B2 (en) 2009-09-11 2014-08-26 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8822700B2 (en) 2009-09-11 2014-09-02 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8703938B2 (en) * 2009-09-11 2014-04-22 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8759332B2 (en) * 2009-09-11 2014-06-24 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US9156818B2 (en) 2009-09-11 2015-10-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
UA108211C2 (en) 2009-11-04 2015-04-10 Янссен Рід Айрленд Benzimidazole imidazole derivatives
US20110274648A1 (en) * 2009-11-11 2011-11-10 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110269956A1 (en) 2009-11-11 2011-11-03 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110281910A1 (en) * 2009-11-12 2011-11-17 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
EP2507232B1 (en) * 2009-12-04 2019-03-20 National Health Research Institutes Proline derivatives
EP2512480A4 (en) * 2009-12-14 2013-05-15 Enanta Pharm Inc Hepatitis c virus inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
NZ600608A (en) * 2009-12-18 2015-01-30 Idenix Pharmaceuticals Inc 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors
US20110152246A1 (en) * 2009-12-18 2011-06-23 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
MX2012007420A (en) * 2009-12-24 2012-07-23 Vertex Pharma Analogues for the treatment or prevention of flavivirus infections.
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EA201201031A1 (en) 2010-01-25 2013-02-28 Энанта Фармасьютиклз, Инк. HEPATITIS C VIRUS INHIBITORS
US8933110B2 (en) 2010-01-25 2015-01-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
EP2528926A4 (en) * 2010-01-28 2013-06-19 Boehringer Ingelheim Int Hepatitis c inhibitor compounds
US8623814B2 (en) * 2010-02-23 2014-01-07 Enanta Pharmaceuticals, Inc. Antiviral agents
US8178531B2 (en) * 2010-02-23 2012-05-15 Enanta Pharmaceuticals, Inc. Antiviral agents
CA2791630A1 (en) * 2010-03-04 2011-09-09 Enanta Pharmaceuticals, Inc. Combination pharmaceutical agents as inhibitors of hcv replication
AU2011232331A1 (en) * 2010-03-24 2012-10-11 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of Flavivirus infections
WO2011119860A1 (en) * 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
US9127021B2 (en) 2010-04-09 2015-09-08 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US9125904B1 (en) 2010-05-11 2015-09-08 Achillion Pharmaceuticals, Inc. Biphenyl imidazoles and related compounds useful for treating HCV infections
CA2800530A1 (en) * 2010-05-28 2011-12-01 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
US8778938B2 (en) 2010-06-04 2014-07-15 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US20130310427A1 (en) * 2010-06-09 2013-11-21 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a protein
NZ605440A (en) 2010-06-10 2014-05-30 Abbvie Bahamas Ltd Solid compositions comprising an hcv inhibitor
US20120195857A1 (en) * 2010-08-12 2012-08-02 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
EP2603080A4 (en) 2010-08-12 2014-01-22 Enanta Pharm Inc Hepatitis c virus inhibitors
WO2012020036A1 (en) * 2010-08-13 2012-02-16 F. Hoffmann-La Roche Ag Hepatitis c virus inhibitors
EP2616461A4 (en) 2010-08-26 2014-03-26 Rfs Pharma Llc Potent and selective inhibitors of hepatitis c virus
US8999967B2 (en) 2010-09-29 2015-04-07 Presidio Pharmaceuticals, Inc. Tricyclic fused ring inhibitors of hepatitis C
KR20190140486A (en) * 2010-11-17 2019-12-19 길리애드 파마셋 엘엘씨 Antiviral compounds
RU2452735C1 (en) * 2010-11-30 2012-06-10 Александр Васильевич Иващенко Substituted azoles, antiviral active component, pharmaceutical composition, synthesis and application method
US20140343286A1 (en) * 2010-12-15 2014-11-20 Allan C. Krueger Anti-viral compounds
EP2651923A4 (en) * 2010-12-15 2014-06-18 Abbvie Inc Anti-viral compounds
US20150232455A1 (en) * 2010-12-15 2015-08-20 Allan C. Krueger Anti-viral compounds
US20130273005A1 (en) 2010-12-20 2013-10-17 Gilead Sciences, Inc. Methods for treating hcv
WO2012087976A2 (en) * 2010-12-21 2012-06-28 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
US8552047B2 (en) 2011-02-07 2013-10-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
JP2012188400A (en) * 2011-03-11 2012-10-04 Tosoh Corp Method for producing dithienobenzodithiophene
WO2012122716A1 (en) 2011-03-17 2012-09-20 Merck Sharp & Dohme Corp. Tetracyclic xanthene derivatives and methods of use thereof for treatment of viral diseases
US8835456B1 (en) 2011-03-18 2014-09-16 Achillion Pharmaceuticals, Inc. NS5A inhibitors useful for treating HCV
US20120252721A1 (en) * 2011-03-31 2012-10-04 Idenix Pharmaceuticals, Inc. Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor
US9546160B2 (en) * 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
JP5669984B2 (en) 2011-05-18 2015-02-18 エナンタ ファーマシューティカルズ インコーポレイテッド Process for producing 5-azaspiro [2.4] heptane-6-carboxylic acid and derivatives thereof
AP2013007263A0 (en) 2011-05-27 2013-11-30 Achillion Pharmaceuticals Inc Substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenesuseful for treating HCV infections
KR20140053166A (en) 2011-07-09 2014-05-07 선샤인 레이크 파르마 컴퍼니 리미티드 Spiro compounds as hepatitis c virus inhibitors
WO2013021344A1 (en) 2011-08-08 2013-02-14 Lupin Limited Imidazole derivatives as antiviral agents
WO2013025975A1 (en) * 2011-08-17 2013-02-21 Glaxosmithkline Llc Combination treatments for hepatitis c
EP2747569A4 (en) * 2011-08-24 2015-07-08 Glaxosmithkline Llc Combination treatments for hepatitis c
WO2013030750A1 (en) 2011-09-01 2013-03-07 Lupin Limited Antiviral compounds
PL2709613T5 (en) 2011-09-16 2020-12-14 Gilead Pharmasset Llc Methods for treating hcv
UY34402A (en) 2011-10-21 2013-05-31 Abbvie Inc METHODS FOR HCV TREATMENT
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
CN104023726A (en) * 2011-10-21 2014-09-03 艾伯维公司 Mono (PSI-7977) or combination treatment of DAAs for use in treating HCV
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
AR088630A1 (en) 2011-11-03 2014-06-25 Theravance Inc HEPATITIS C VIRUS INHIBITORS
PL2635588T3 (en) * 2011-11-16 2015-10-30 Gilead Pharmasset Llc Condensed imidazolylimidazoles as antiviral compounds
US9126986B2 (en) 2011-12-28 2015-09-08 Janssen Sciences Ireland Uc Hetero-bicyclic derivatives as HCV inhibitors
US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
CA2857339C (en) * 2011-12-29 2015-11-17 Abbvie Inc. Solid compositions comprising an hcv inhibitor
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2013118097A1 (en) * 2012-02-10 2013-08-15 Lupin Limited Antiviral compounds with a dibenzooxaheterocycle moiety
MX2014009850A (en) * 2012-02-14 2015-03-10 Univ Georgia Spiro [2.4]heptanes for treatment of flaviviridae infections.
ITMI20120424A1 (en) 2012-03-19 2013-09-20 Rottapharm Spa CHEMICAL COMPOUNDS
CN104302636B (en) 2012-04-25 2017-03-29 施万生物制药研发Ip有限责任公司 Hepatitis C virus inhibitor
CN104302639B (en) 2012-04-25 2017-03-29 施万生物制药研发Ip有限责任公司 As the piperazine piperidine compounds of hepatitis C virus inhibitor
US20130309196A1 (en) 2012-05-16 2013-11-21 Gilead Sciences, Inc. Antiviral compounds
US9079887B2 (en) * 2012-05-16 2015-07-14 Gilead Sciences, Inc. Antiviral compounds
US9056860B2 (en) * 2012-06-05 2015-06-16 Gilead Pharmasset Llc Synthesis of antiviral compound
US8969588B2 (en) * 2012-06-05 2015-03-03 Gilead Pharmasset Llc Solid forms of an antiviral compound
TWI610916B (en) * 2012-08-03 2018-01-11 廣東東陽光藥業有限公司 Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceuticals applications thereof
TW201412709A (en) * 2012-09-28 2014-04-01 Sunshine Lake Pharma Co Ltd Spiro ring compounds as hepatitis c virus (HCV) inhibitors and pharmaceutical applications thereof
CN103848818B (en) * 2012-11-29 2017-03-15 广东东阳光药业有限公司 Simultaneously cycle compound, pharmaceutical composition and their applications in medicine as hepatitis c inhibitor
WO2014082381A1 (en) * 2012-11-29 2014-06-05 Sunshine Lake Pharma Co., Ltd. Spiro ring compounds as hepatitis c virus inhibitors, pharmaceutical compositions and uses thereof
WO2014082379A1 (en) * 2012-11-29 2014-06-05 Sunshine Lake Pharma Co.,Ltd. Spiro ring compound as hepatitis c virus (hcv) inhibitor and uses thereof field of the invention
CN103880823B (en) * 2012-12-21 2017-12-05 广东东阳光药业有限公司 Application as the spiro-compound of hepatitis c inhibitor and its in medicine
SG10201706949VA (en) 2013-01-31 2017-09-28 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
RU2507201C1 (en) * 2013-02-07 2014-02-20 Александр Васильевич Иващенко Alkyl [(s)-1-((s)-2-{5-[4-(4-{2-[(s)-1-((s)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3h-imidazol-4-yl}-buta-1,3-diinyl)-phenyl]-1h-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamate naphthalene-1,5-disulphonate, pharmaceutical composition, medicinal agent, method of treating viral diseases
RU2518369C1 (en) * 2013-02-07 2014-06-10 Общество с ограниченной ответственностью "Интеллектуальный Диалог" Alkyl [2-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3h-imidazol-4-yl}-phenyl)-buta-1,3-diinyl]-1h-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamate, pharmaceutical composition, medication, method of treating viral diseases
TW201439060A (en) * 2013-02-27 2014-10-16 Sunshine Lake Pharma Co Ltd Bridged ring compounds as HCV inhibitors, pharmaceutical compositions and uses thereof
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
US20140357595A1 (en) * 2013-06-04 2014-12-04 Gilead Pharmasset Llc Methods of preventing and treating recurrence of a hepatitis c virus infection in a subject after the subject has received a liver transplant
CN111116563B (en) * 2013-06-06 2023-07-04 上海爱博医药科技有限公司 Compound for inhibiting hepatitis C virus, pharmaceutical composition and application thereof
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US20150023913A1 (en) 2013-07-02 2015-01-22 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
JP2016527232A (en) 2013-07-17 2016-09-08 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Combinations comprising biphenyl derivatives for use in the treatment of HCV
MX2016002185A (en) 2013-08-27 2016-06-06 Gilead Pharmasset Llc Combination formulation of two antiviral compounds.
CN104418785A (en) * 2013-09-05 2015-03-18 浙江九洲药业股份有限公司 Preparation method of drug intermediate
US20160229866A1 (en) 2013-09-20 2016-08-11 Idenix Pharmaceuticals Inc. Hepatitis c virus inhibitors
CN104610272B (en) * 2013-11-05 2017-03-29 上海唐润医药科技有限公司 Ring-type flavones or isoflavonoid and application thereof
KR101561964B1 (en) 2013-11-15 2015-10-20 한국과학기술연구원 Oxazolidinone derivatives and composition for preventing or treating Hepatitis C containing the same
US20150150897A1 (en) 2013-12-02 2015-06-04 Gilead Pharmasset Llc Methods of treating hepatitis c virus infection in subjects with cirrhosis
TW201609785A (en) 2013-12-23 2016-03-16 吉李德製藥公司 Solid forms of an antiviral compound
CN104725365B (en) * 2013-12-23 2019-02-26 南京圣和药业股份有限公司 Hepatitis C virus inhibitors and its application
CN105873922B (en) * 2013-12-31 2018-08-14 南京圣和药业股份有限公司 Tetra- fluoro- 9,10 dihydro phenanthrene class hepatitis C virus inhibitors of 9,9,10,10- and its application
WO2015103490A1 (en) 2014-01-03 2015-07-09 Abbvie, Inc. Solid antiviral dosage forms
CN104803989B (en) * 2014-01-23 2017-12-22 广东东阳光药业有限公司 Application as the endocyclic compound of hepatitis c inhibitor and its in medicine
CN104860931A (en) * 2014-02-21 2015-08-26 常州寅盛药业有限公司 Hepatitis C virus inhibitors and pharmaceutical uses thereof
CN108084172A (en) * 2014-02-21 2018-05-29 常州寅盛药业有限公司 Anti- hepatitis C virus compound
WO2015184644A1 (en) * 2014-06-06 2015-12-10 爱博新药研发(上海)有限公司 Compounds and pharmaceutical compositions for inhibiting hepatitis c virus, and uses thereof
CN104140417B (en) * 2014-06-11 2016-04-06 苏州景泓生物技术有限公司 The synthetic method of the compound in advance of the intermediate of synthesis GS5885
TWI721947B (en) 2014-06-11 2021-03-21 美商基利法瑪席特有限責任公司 Solid forms of an antiviral compound
CN105524049B (en) * 2014-09-28 2018-11-06 正大天晴药业集团股份有限公司 Deuterated hepatitis C virus NS 5 A protein on NS inhibitor
CN104513147B (en) * 2014-11-20 2016-05-11 上海众强药业有限公司 The preparation method of fluorenes ethanone derivatives
CN105693700B (en) * 2014-12-16 2019-01-04 广东东阳光药业有限公司 Endocyclic compound and preparation method thereof as hepatitis c inhibitor
WO2016103232A1 (en) * 2014-12-24 2016-06-30 Granules India Limited An improved process for the preparation of hcv inhibitor
CN104530016A (en) * 2014-12-25 2015-04-22 上海泓博智源医药技术有限公司 Method for preparing Ledipasvir and intermediates of method for preparing Ledipasvir
KR20230130175A (en) 2014-12-26 2023-09-11 에모리 유니버시티 N4-hydroxycytidine and derivatives and anti-viral uses related thereto
CN107427495A (en) 2015-02-13 2017-12-01 桑多斯股份公司 Include Lei Dipawei and Suo Feibuwei pharmaceutical composition
CN105985355B (en) * 2015-03-01 2020-05-05 南京圣和药业股份有限公司 Fused tricyclic hepatitis virus inhibitor and application thereof
MD20170081A2 (en) 2015-03-04 2018-03-31 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-D]pyrimidine compounds
WO2016145269A1 (en) 2015-03-12 2016-09-15 Teva Pharmaceuticals International Gmbh Solid state forms ledipasvir and processes for preparation of ledipasvir
CN104829599B (en) * 2015-03-17 2017-06-09 上海众强药业有限公司 The preparation method and the midbody compound for preparing Lei Dipawei of Lei Dipawei and its derivative
US20160375017A1 (en) 2015-06-26 2016-12-29 Abbvie Inc. Solid Pharmaceutical Compositions for Treating HCV
CN105017228A (en) * 2015-07-03 2015-11-04 上海众强药业有限公司 Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor
MA43294A1 (en) 2015-07-24 2020-04-30 Newlink Genetics Corp 1-methyl-d-tryptophan salts and prodrugs
WO2017023631A1 (en) 2015-08-06 2017-02-09 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
KR101919194B1 (en) * 2015-09-15 2018-11-15 주식회사 엘지화학 Heterocyclic compound and organic light emitting device comprising the same
CN105294713A (en) * 2015-10-09 2016-02-03 重庆康施恩化工有限公司 Velpatasvir intermediate and preparation method thereof
WO2017072596A1 (en) 2015-10-26 2017-05-04 Optimus Drugs (P) Ltd An improved process for the preparation of ledipasvir
WO2017072714A1 (en) 2015-10-30 2017-05-04 Lupin Limited Stable ledipasvir premix and process of preparation thereof
CN108349945B (en) * 2015-11-06 2021-10-29 江苏豪森药业集团有限公司 HCV inhibitor, preparation method and application thereof
CN106117187B (en) * 2016-01-12 2019-01-01 深圳市塔吉瑞生物医药有限公司 A kind of hepatitis C virus inhibitors, pharmaceutical composition and its application
US20190062332A1 (en) * 2016-02-01 2019-02-28 Lupin Limited Process for the preparation of ledipasvir and intermediates thereof
WO2017145028A1 (en) * 2016-02-26 2017-08-31 Glenmark Pharmaceuticals Limited Process for preparation of ledipasvir
WO2017184670A2 (en) 2016-04-22 2017-10-26 Gilead Sciences, Inc. Methods for treating zika virus infections
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
WO2017197055A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Heterocyclic degronimers for target protein degradation
EP3455218A4 (en) 2016-05-10 2019-12-18 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
CN109562113A (en) 2016-05-10 2019-04-02 C4医药公司 Loop coil degron body for target protein degradation
WO2017195147A1 (en) 2016-05-12 2017-11-16 Lupin Limited Process for the preparation of ledipasvir and intermediates thereof
BR112018073858A2 (en) 2016-05-27 2019-02-26 Gilead Sciences, Inc. methods for treating hepatitis b virus infections using ns5a, ns5b or ns3 inhibitors
BR102017011025A2 (en) 2016-06-02 2017-12-19 Gilead Pharmasset Llc FORMULATION OF COMBINATION OF THREE ANTIVIRAL COMPOUNDS
CN107663196A (en) * 2016-07-27 2018-02-06 广东东阳光药业有限公司 The method of prepare compound
WO2018035410A1 (en) * 2016-08-19 2018-02-22 Temple University-Of The Commonwealth System Of Higher Education Compositions and methods of treatment using expanded-size dna analogs
US10640499B2 (en) 2016-09-02 2020-05-05 Gilead Sciences, Inc. Toll like receptor modulator compounds
CA3035346A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Toll like receptor modulator compounds
CN106632275B (en) * 2016-12-20 2018-03-06 上海同昌生物医药科技有限公司 The preparation method of Lei Dipawei a kind of and the intermediate for preparing Lei Dipawei
RU2650610C1 (en) 2017-02-28 2018-04-16 Васильевич Иващенко Александр Antiviral composition and method of its application
US10392370B2 (en) 2017-03-13 2019-08-27 Optimus Drugs Pvt Ltd Process for the preparation of Daclatasvir dihydrochloride and its intermediates
JOP20180040A1 (en) 2017-04-20 2019-01-30 Gilead Sciences Inc Pd-1/pd-l1 inhibitors
CA3063288A1 (en) 2017-05-12 2018-11-15 Mavalon Therapeutics Limited Substituted heterocyclic compounds as allosteric modulators of group ii metabotropic glutamate receptors
AU2018378832B9 (en) 2017-12-07 2021-05-27 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
AU2019222644B2 (en) 2018-02-13 2021-04-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
KR20210042264A (en) * 2018-05-15 2021-04-19 유니버시티 오브 루이빌 리서치 파운데이션, 인코포레이티드 Urolitin A and its derivatives for use in therapy
JP7105359B2 (en) 2018-07-13 2022-07-22 ギリアード サイエンシーズ， インコーポレイテッド PD-1/PD-L1 inhibitor
AU2019366355B2 (en) 2018-10-24 2022-10-13 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
TW202106677A (en) * 2019-04-25 2021-02-16 美商貝達醫藥公司 Dicarbamate inhibitors of ns5a for the treatment of hepatitis c virus infections
WO2020255038A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives
US20230218644A1 (en) 2020-04-16 2023-07-13 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
EP4079748A1 (en) 2021-04-23 2022-10-26 Insusense ApS Modulators of sortilin activity
EP4089102A1 (en) 2021-05-14 2022-11-16 Insusense ApS Modulators of sortilin activity
CA3219397A1 (en) * 2021-05-21 2022-11-24 Gilead Sciences, Inc. Tetracyclic compounds for the treatment of zika virus infection
IL309732A (en) 2021-07-09 2024-02-01 Aligos Therapeutics Inc Anti-viral compounds
US20230140238A1 (en) * 2021-09-17 2023-05-04 Aligos Therapeutics, Inc. Anti-viral compounds
WO2023154528A1 (en) * 2022-02-11 2023-08-17 Wave Life Sciences Ltd. Stereoselective technologies for chiral compounds

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021928A2 (en) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2008021927A2 (en) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2008144380A1 (en) * 2007-05-17 2008-11-27 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2009020828A1 (en) * 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt
WO2009102568A1 (en) * 2008-02-13 2009-08-20 Bristol-Myers Squibb Company Conformationally restricted biphenyl derivatives for use as hepatitis c virus inhibitors
WO2010017401A1 (en) * 2008-08-07 2010-02-11 Bristol-Myers Squibb Company Bi-1h-benzimidazoles as hepatitis c virus inhibitors
WO2010065674A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
WO2010065681A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a

Family Cites Families (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816570A (en) 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4968788A (en) 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
ES2083580T3 (en) 1990-06-13 1996-04-16 Arnold Glazier PHOSPHORIC DRUGS.
DK0481214T3 (en) 1990-09-14 1999-02-22 Acad Of Science Czech Republic Prophylactic drugs of phosphonates
US5543523A (en) 1994-11-15 1996-08-06 Regents Of The University Of Minnesota Method and intermediates for the synthesis of korupensamines
ATE516293T1 (en) 2004-07-16 2011-07-15 Gilead Sciences Inc ANTIVIRAL COMPOUNDS
US7323447B2 (en) * 2005-02-08 2008-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8143288B2 (en) 2005-06-06 2012-03-27 Bristol-Myers Squibb Company Inhibitors of HCV replication
US8303944B2 (en) * 2006-08-11 2012-11-06 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
CA2692248A1 (en) * 2007-06-19 2008-12-24 Kyorin Pharmaceutical Co., Ltd. Pyridazinone derivative and pde inhibitor containing the same as active ingredient
US7728027B2 (en) 2007-08-08 2010-06-01 Bristol-Myers Squibb Company Process for synthesizing compounds useful for treating hepatitis C
EP2250163B1 (en) 2008-02-12 2012-03-28 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
CA2715839C (en) 2008-02-13 2014-12-09 Bristol-Myers Squibb Company Imidazolyl biphenyl imidazoles as hepatitis c virus inhibitors
US8147818B2 (en) * 2008-02-13 2012-04-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
GB2457659A (en) 2008-02-19 2009-08-26 Malcolm Mulheron Foldable meal tray
WO2010004843A1 (en) 2008-07-08 2010-01-14 Ntn株式会社 Reduction device
WO2010004343A1 (en) 2008-07-10 2010-01-14 Prosidion Limited Piperidinyl gpcr agonists
US8383094B2 (en) * 2008-10-01 2013-02-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010062821A1 (en) 2008-11-28 2010-06-03 Glaxosmithkline Llc Anti-viral compounds, compositions, and methods of use
EP2393359A4 (en) 2009-02-09 2012-10-03 Enanta Pharm Inc Linked dibenzimidazole derivatives
WO2010096462A1 (en) 2009-02-17 2010-08-26 Enanta Pharmaceuticals, Inc Linked diimidazole derivatives
TWI438200B (en) 2009-02-17 2014-05-21 必治妥美雅史谷比公司 Hepatitis c virus inhibitors
US20120040977A1 (en) 2009-02-23 2012-02-16 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
UY32462A (en) 2009-02-23 2010-09-30 Arrow Therapeutics Ltd NEW BIFENYLL DERIVATIVES FOR HEPATITIS C 644 VIRUS INFECTION TREATMENT
MX2011008982A (en) 2009-02-27 2011-09-15 Enata Pharmaceuticals Inc Hepatitis c virus inhibitors.
JP2012521359A (en) 2009-03-20 2012-09-13 アリオス バイオファーマ インク． Substituted nucleoside and nucleotide analogs
KR20110131312A (en) 2009-03-27 2011-12-06 프레시디오 파마슈티칼스, 인코포레이티드 Fused ring inhibitors of hepatitis c
EP2410841A4 (en) 2009-03-27 2012-10-24 Presidio Pharmaceuticals Inc Substituted bicyclic hcv inhibitors
SG10201402969QA (en) 2009-03-27 2014-09-26 Merck Sharp & Dohme Inhibitors of hepatitis c virus replication
US8796466B2 (en) * 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
TWI476190B (en) * 2009-03-30 2015-03-11 必治妥美雅史谷比公司 Hepatitis c virus inhibitors
TW201038559A (en) 2009-04-09 2010-11-01 Bristol Myers Squibb Co Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
MX2011010905A (en) 2009-04-15 2011-11-01 Abbott Lab Anti-viral compounds.
CN102414199B (en) 2009-04-24 2014-03-05 泰博特克药品公司 Diaryl ethers
US9139569B2 (en) * 2009-05-12 2015-09-22 Merck Sharp & Dohme Corp. Fused tricyclic aryl compounds useful for the treatment of viral diseases
EP2857394A1 (en) * 2009-05-13 2015-04-08 Gilead Pharmasset LLC Antiviral compounds
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
AU2010253790A1 (en) 2009-05-29 2011-12-15 Merck Sharp & Dohme Corp. Antiviral compounds composed of three aligned aryl moieties to treat diseases such as Hepatitis C
WO2010138791A1 (en) 2009-05-29 2010-12-02 Schering Corporation Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2337781B1 (en) * 2009-06-11 2014-07-23 AbbVie Bahamas Ltd. Anti-viral compounds to treat hcv infection
US8221737B2 (en) * 2009-06-16 2012-07-17 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2010148006A1 (en) 2009-06-16 2010-12-23 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
WO2011004276A1 (en) 2009-07-06 2011-01-13 Pfizer Limited Hepatitis c virus inhibitors
AU2010274001A1 (en) 2009-07-16 2012-02-23 Vertex Pharmaceuticals Incorporated Benzimidazole analogues for the treatment or prevention of Flavivirus infections
AU2010280711A1 (en) 2009-08-07 2012-02-09 Janssen Sciences Ireland Uc Phenyl ethynyl derivatives as hepatitis C virus inhibitors
CA2768638A1 (en) 2009-08-07 2011-02-10 Tibotec Pharmaceuticals Bis-benzimidazole derivatives as hepatitis c virus inhibitors
FR2949465B1 (en) 2009-09-01 2011-08-12 Pf Medicament CHROMIUM DERIVATIVES, PROCESS FOR PREPARING THEM AND THERAPEUTIC APPLICATIONS THEREOF
US20120172368A1 (en) 2009-09-03 2012-07-05 Koen Vandyck Bis-Benzimidazole Derivatives
SG178952A1 (en) 2009-09-04 2012-04-27 Glaxosmithkline Llc Chemical compounds
WO2011031934A1 (en) 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US9156818B2 (en) 2009-09-11 2015-10-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8415374B2 (en) 2009-10-12 2013-04-09 Bristol-Myers Squibb Company Combinations of hepatitis C virus inhibitors
WO2011050146A1 (en) 2009-10-23 2011-04-28 Glaxosmithkline Llc Chemical compounds
UA108211C2 (en) 2009-11-04 2015-04-10 Янссен Рід Айрленд Benzimidazole imidazole derivatives
US20110274648A1 (en) 2009-11-11 2011-11-10 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110269956A1 (en) 2009-11-11 2011-11-03 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110281910A1 (en) 2009-11-12 2011-11-17 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
WO2011066241A1 (en) 2009-11-25 2011-06-03 Schering Corporation Fused tricyclic compounds and derivatives thereof useful for the treatment of viral diseases
US20110137633A1 (en) * 2009-12-03 2011-06-09 Abbott Laboratories Anti-viral compounds and methods of identifying the same
EP2512480A4 (en) * 2009-12-14 2013-05-15 Enanta Pharm Inc Hepatitis c virus inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US20110152246A1 (en) 2009-12-18 2011-06-23 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
NZ600608A (en) * 2009-12-18 2015-01-30 Idenix Pharmaceuticals Inc 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors
US20130156731A1 (en) 2009-12-22 2013-06-20 Kevin X. Chen Fused tricyclic compounds and methods of use thereof for the treatment of viral diseas
MX2012007420A (en) 2009-12-24 2012-07-23 Vertex Pharma Analogues for the treatment or prevention of flavivirus infections.
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2011091446A1 (en) 2010-01-22 2011-07-28 Glaxosmithkline Llc Chemical compounds
ES2558554T3 (en) 2010-03-09 2016-02-05 Merck Sharp & Dohme Corp. Condensed tricyclic silyl compounds and methods of their use for the treatment of viral diseases
US20110312996A1 (en) 2010-05-17 2011-12-22 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
CA2797872A1 (en) * 2010-05-21 2011-11-24 Gilead Sciences, Inc. Heterocyclic flaviviridae virus inhibitors
WO2011156757A1 (en) * 2010-06-10 2011-12-15 Gilead Sciences, Inc. Combination of anti-hcv compounds with ribavirin for the treatment of hcv
EP2616461A4 (en) 2010-08-26 2014-03-26 Rfs Pharma Llc Potent and selective inhibitors of hepatitis c virus
WO2012041014A1 (en) 2010-09-29 2012-04-05 Merck Sharp & Dohme Corp. Tetracyclic indole derivatives for treating hepatitis c virus infection
WO2012048421A1 (en) 2010-10-14 2012-04-19 Boehringer Ingelheim International Gmbh Hepatitis c inhibitor compounds
KR20190140486A (en) 2010-11-17 2019-12-19 길리애드 파마셋 엘엘씨 Antiviral compounds
US20130273005A1 (en) 2010-12-20 2013-10-17 Gilead Sciences, Inc. Methods for treating hcv
WO2012087976A2 (en) 2010-12-21 2012-06-28 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
PL2709613T5 (en) * 2011-09-16 2020-12-14 Gilead Pharmasset Llc Methods for treating hcv
PL2635588T3 (en) 2011-11-16 2015-10-30 Gilead Pharmasset Llc Condensed imidazolylimidazoles as antiviral compounds
US8969588B2 (en) * 2012-06-05 2015-03-03 Gilead Pharmasset Llc Solid forms of an antiviral compound
US8841340B2 (en) * 2012-08-17 2014-09-23 Gilead Sciences, Inc. Solid forms of an antiviral compound

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021928A2 (en) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2008021927A2 (en) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2008144380A1 (en) * 2007-05-17 2008-11-27 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2009020828A1 (en) * 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt
WO2009102568A1 (en) * 2008-02-13 2009-08-20 Bristol-Myers Squibb Company Conformationally restricted biphenyl derivatives for use as hepatitis c virus inhibitors
WO2010017401A1 (en) * 2008-08-07 2010-02-11 Bristol-Myers Squibb Company Bi-1h-benzimidazoles as hepatitis c virus inhibitors
WO2010065674A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
WO2010065681A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
WO2010065668A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a

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